Malaria has become a major threat to children, pregnant women and the aging in Cameroon due to single and multiple drug resistance in Plasmodium falciparum malaria. New drugs, vector control measures and a malaria vaccine are a necessity. The need to characterize and understand the components of acquired immunity to malaria are urgent if we are to develop; a successful malaria vaccine that can be used in malaria endemic areas. Natural immunity to malaria does occur, albeit slowly, taking many years, and even then may not be complete. The slow development of immunity may be due to the differential and age-related responses to immunodominant, variant and conserved, subdominant P. falciparum immunologically relevant proteins. We and others have demonstrated that humoral and cellular responses to MSP-1, MSP-2, AMA-1, may be important for the induction of protective immunity. We hypothesize that children respond predominantly to immunodominant variant epitopes, leading to incomplete immunity, and older children and adults respond to conserved epitopes resulting in long term protective immunity. To test our hypotheses, we will examine over five years the cellular and humoral immune responses to these antigens in a rural study population including, infants ages 1-5 years, children in age groups of 6-10 and 10- 15 years, and adults aged 16-45 who are naturally exposed to malaria. We will also examine cellular immune responses to both conserved and variant epitopes from MSP-1, MSA-2, AND AMA-1 candidate vaccine antigens. The immune responses will be correlated with HLA type to determine whether HLA effects the specificity and/or rate of development of protective immunity. This study will be carried out through a unique partnership between researchers in the laboratory and in the field. Data provided on the immune status of the population may help identify those effector mechanisms required for protective immunity. Also, data from this study may help in the development of intervention strategies that will contribute to the control of malaria in Cameroon.